The vaccine cavalry is on its way, but what does the future really look like?

The vaccine cavalry is on its way, but what does the future really look like?

After the emergence of COVID-19 in China at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has rapidly spread across the globe causing mass medical and economic devastation.

As the global mass vaccination programme is rolled out and Cryoniss launches its new COVID sample and vaccine storage service, we thought it a timely opportunity to reflect on the outbreak of the pandemic.

Background to the SARS-COV-2 virus and the pathology of the Covid-19 disease

 

SARS-COV-2 is an enveloped, single-stranded 30 kb RNA virus.  Structurally, it consists of four main protein components: Spike (S), membrane (M), envelope (E) and nucleocapsid (N). The mechanism of viral entry includes binding of the spike S1 subunit to the angiotensin converting enzyme 2 (ACE2) on host cells, which is highly expressed in lung epithelial cells, alongside most other cell types.  This binding induces proteolytic cleavage of the spike subunits at furin cleavage sites that stabilise the binding of SARS-COV-2 for fusion to the host cell, enabling viral entry and subsequent replication.

Disease symptoms vary from patients who are asymptomatic, through those presenting mild ‘flu-like’ symptoms to those experiencing acute respiratory distress syndrome (ARDS) and other systemic pathological events.  This variety of symptoms has been attributed to the death of and damage to lung epithelial cells caused by viral entry and replication, alongside the regulatory role of ACE2 during renin-angiotensin-aldosterone system (RAAS) overactivation.  The RAAS system is a core of these three hormones that contribute to blood pressure control, fluid and electrolyte homeostasis.  Imbalance in these hormones can lead to, or indeed treat, hypotension, heart failure, atherosclerosis and diabetes mellitus.

Covid-19 vaccine race to the finish

As the vaccine roll out in the UK began in December, the government and scientific community grappled with public concerns over the safety of the vaccine, due in part to  its unusually quick development and approval, particularly when considering vaccines historically take in excess of 10 years to be approved.

Vaccinations have been a standard weapon in our armoury against viruses since Edward Jenner used live cowpox to immunise people against smallpox in 1796, although science has clearly advanced significantly since this rudimentary effort.  Not only have we seen the leading experts in viral structure, biology and epidemiology galvanise to understand, detect and track this new virus, in addition, vaccine design, safety profiling, manufacturing and logistics roll out have all combined on an impressive and unprecedented scale.  Collaborations and partnerships between government, regulatory authorities and the scientific community around the world, both in terms of funding and pooling knowledge, together with our ability to streamline the production process based on past experience with vaccine development and our ability to invest at scale well ahead of clinical studies have all proved invaluable. 

The race to produce the first effective and safe vaccine was quickly won by Pfizer-BioNTech and their BNT162b2 lipid nanoparticle-formulated nucleoside-modified mRNA vaccine encoding full length SARS-COV-2 spike protein.

Clinical study of this vaccine enrolled over 65 thousand people across numerous countries and of varied demographics, including Black, Asian and Minority Ethnicities. Safety profile from this multinational trial revealed only mild side effects including headaches and pain at the site of injection.

This vaccine delivers the mRNA intramuscularly to induce endogenously driven spike protein production. Both neutralising antibodies and cellular immune responses are elicited in response to spike antigens, in an effort to build immunity to SARS-COV- 2 without viral infection and the symptoms which come with it.

The Oxford AstraZeneca vaccine (AZD1222) soon followed, providing immunity through delivery of the SARS-COV-2 gene (DNA) through an adenovirus transmission vector which encourages our cells to endogenously produce spike protein.  This ensures that an immune response will naturally be mounted, inducing a T cell response that confers long-term immunity. Side effects are similar to that of the Pfizer vaccine - the only other notable difference being its storage conditions.  The Oxford-AstraZeneca vaccine can be stored at 2-8 degrees Celsius, compared to Pfizer vaccine suggested storage of -70 degrees Celsius.

Just last month, the Moderna mRNA-1273 vaccine was approved by the Medicines and Healthcare products Regulatory Agency.  This is a novel, lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS-CoV-2.

These are just the vaccines approved to date; however, there are a large number of other vaccines being developed by Johnson & Johnson, GSK/Sanofi, Novavax, Janssen and Valneva for example.

The majority of vaccines currently work with a two-dose regiment to boost the immune response. Dosing intervals vary from 4-12 weeks but longer dosing intervals gives the immune response time to mature and proves more effective in increasing immunity.  Despite this, Johnson & Johnson are potentially set for approval of a single dose mRNA vaccine (JNJ-78436735).  It will be interesting to compare its efficiency with the double-dosing system and also to compare its acceptance by and uptake into the population, pointing perhaps to whether a single dose would be favoured.

What does the post-Covid-19 vaccine world look like?

This leads to the key questions on everyone’s minds….  Given the expensive development of these vaccines, will the vaccines prevent further infection and transmission?  Will they work against current and future variants?  And indeed, how long will they remain effective?

The latest studies have shown that antibodies to SARS-COV-2 (including neutralising antibodies) persist in the serum for at least 6-7 months in 90% of patients tested.  Typical antibody kinetics have been seen in Covid-19 patients, in both T- and B- cell responses, including the formation of long-lived memory cells. 

The most recent hurdle in the fight against COVID-19 is the development of several new strains originating around the globe.  Mutations are a natural part of viral evolution, and the majority will have little impact on the epidemiology or severity of the disease.  These genetic mutations, however, have become a useful tool in tracking the disease, which is the purpose of the Covid-19 Genomics UK Consortium (COG).  They have analysed genomes of ~214,039 viral samples and have identified more than 1,300 instances of a Covid-19 virus entering the UK and spreading. 

Originating in Kent in December 2020, the ‘first variant under investigation’ showed an increased transmission rate of 70% when compared to existing strains.  Analysis showed that this new variant, VUI-202012/01, had 23 mutations, and critically a N501Y mutation in the spike protein, despite the presence of proof-reading enzyme (nsp14).  To date, there are now 4,000 reported spike protein mutations in SARS-COV-2. 

It is certainly possible that spike protein mutations may increase the pathogenicity or infectivity of the virus.  For example, another frequently referenced spike mutation is D614G.  This variant has been shown to be linked to increased viral load but does not impact disease severity.  Korber et al., interrogated cryo-electron microscopy analyses to study the D614G substitution on the S1 subunit.  It is believed that D614 forms a hydrogen bond with the T859 residue on S2 protomer.  The G614 mutation is believed to disrupt this bond, potentially affecting glycosylation in the adjacent N616 site, thereby weakening the stability of the trimer.  This also has the impact that the intra-protomer distance between the backbone amine of 614 and backbone of carboxyl group of residue 647 is shortened, subsequently stabilising the C-terminal domain of the protein and resulting in this variant being more likely to assume an ‘open’ conformation, increasing the chances of binding to the host cell ACE2 receptor. 

The new variant has mutations to the spike protein that the three leading vaccines are targeting. However, vaccines produce antibodies against many regions in the spike protein, and therefore it is unlikely that limited genetic viral changes such as these, would render the vaccines useless. Over time however, as more antigenic escape mutations accumulate, it is feasible that the vaccine will require updating in a similar way to that of the seasonal flu jab.  It is also worth noting that a world-wide immunisation programme against Covid-19 will introduce a selective pressure for the virus, potentially driving the development of mutations.

The next question on everyone’s minds is whether these vaccines prevent infection and future transmission.  The general consensus to this last week was, no.  This was initially based upon knowledge of coronavirus vaccines used frequently in domestic animals, inactivated or intramuscular parenteral injections lead to high systemic levels of neutralising antibodies.  However, they have been less efficacious against mucosal viruses and have not prevented viral shedding.

That being said, AstraZeneca-Oxford vaccine Phase III trials, published as a preprint in The Lancet on Monday, not only supported the Government's decision to space out single doses to increase the number of people immunised initially, but also indirectly examined the impact of transmission of the virus post vaccination.  Swabs were taken from all participants on a weekly basis and tested by PCR.  They found that after a single dose PCR positive tests dropped by 67% suggesting a reduction in the burden of infection.

Current research is still ongoing, and consensus may change in the future.  However, if these predictions are correct, the vaccine deployments are undoubtedly going to have a major impact on returning our world to something like normal.   Whilst we cannot escape the fact that Covid-19 will be with us for the foreseeable future, the promise of the vaccines means that at least the future is looking more hopeful! 

SARS-COV-2 will continue to spread, adding to the seroprevalence and mucosal immunity in the population that comes with most people being asymptomatic or presenting mild symptoms.  Cross-reactive immunity will hopefully limit the risk of mutants leading to severe disease.  Whilst vulnerable people will continue to be at risk, this risk will reduce over time, driven by herd immunity and an established vaccination programme. 

The UK Government last week announced the tragic milestone of 100,000 deaths.  We are certainly enduring the worst of the pandemic, and as we hopefully emerge on the other side in the coming months, even when it is almost impossible, we must hold on to the fact that we have a lot to be grateful for.  With the incredible support of all of the keyworkers, what the scientific and medical community has achieved in such a short amount of time is testament to the ingenuity, brilliance and determination of our community.

Olivia

Correct as of 04 Feb 2021

References:

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